This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Antinuclear antibodies of particular specificities are associated with systemic lupus erythematosus-SLE. Preliminary studies implicate IL-4 and the proinflammatory cytokines IL-6, IL-12, and IFNy in the formation of different subsets of autoantibodies. Cytokine overproduction may be a key factor determining the autoantibody phenotype. We have found that autoantibody phenotypes in SLE patients also can change. We hypothesize that cytokine overproduction may be a critical factor determining autoantibody specificity. We will look for human autoantibody phenotypes, defined as groups of autoantibodies produced together more frequently than predicted by chance- Aim 1. Anti-Sm and anti-Ku are strongly associated with one another. The frequencies of these phenotypes will be determined in African-American, Caucasian, and other SLE cohorts. We will determine whether the autoantibody phenotypes correlate with certain patterns of cytokine overproduction-Aim 2. A variety of cytokines will be measured directly in the blood and indirectly in affected tissues through the use of surrogate markers. We will carry out prospective studies to explore the possibility that the overproduction of IFNy, which drives anti-nRNP/Sm autoantibody production in mice, increases the risk of developing a subset of autoantibodies in human lupus-Aim 3. We hypothesize that there may be certain lupus patients who overproduce IFNy. Another group of SLE patients, most commonly Caucasians, may overproduce a different set of cytokines. This may help explain some of the striking serological differences between races. Like murine lupus, human SLE may be several diseases with overlapping clinical manifestations but a different pathogenesis.